Many reports have described a high incidence of a positive red cell antiglobin reaction (direct Coombs test) in patients taking the antihypertensive drug, alph-methyldopa. Based on our previous work showing that cytochrome P-450 generated superoxide anion oxidized alpha-methyldopa to a reactive arylating agent, we were interested to see if human erythrocytes could activate the drug in a similar manner. Incubation of intact or lysed human red cells with H3-alpha-methylled to covalent binding of the drug to red cell constituents. Further studies showed that oxyhemoglobin was required for the binding reaction. Because oxyhemoglobin can be visualized as a ferrihemoglobin-superoxide anion complex similar to the monoreduced form postulated for oxygenated cytochrome P-450 in the liver, we believe that superoxide anion from oxyhemoglobin oxdizes the catechol nucleus of alpha-methyldopa to semiquinone radicals or quinones which covalently bind to the erythrcytes. The denatured macromolecules may then be antigenic and lead to the production of a direct Coombs test and immune hemolysis. The mechanism for this drug allergy is now being studied by attempting to determine the natuue of the antigenic component.